A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis.

AIM: To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice. METHODS: The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined. RESULTS: Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in ß-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the ß2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice. CONCLUSION: BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors.

OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg(-1), BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg(-1) resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors.

ErbB4 (JM-b/CYT-1)-induced expression and phosphorylation of c-Jun is abrogated by human papillomavirus type 16 E5 protein.

Human papillomavirus type 16 E5 (HPV-16 E5) is a highly hydrophobic membrane protein with weak-transforming activity, which is associated with ErbB4 receptor in HPV-16-infected cervical lesions. Presently, we investigated the transforming mechanisms of E5 involving ErbB4 signaling. Firstly, we report a role for ErbB4 (JM-b/CYT-1) receptor that activates c-jun gene expression and phosphorylating at Ser63 and Ser73 of the c-Jun protein in ligand-independent and Ras-c-jun NH(2)-terminal kinase-dependent pathway. Secondly, we show that HPV-16 E5 protein can form a complex with ErbB4 via binding to the extracellular and transmembrane domains of ErbB4 (JM-b/CYT-1). When co-expressing HPV-16 E5 and ErbB4 in cells, E5 can abrogate ErbB4-induced c-Jun protein expression and phosphorylation resulted in increasing cell proliferation compared to ErbB4-expressing cells. The interaction between of HPV-16 E5 and ErbB4 provides more insight into the mechanisms of HPV-16 E5 transformation induction.

Quantitative profile of estrogen receptor variants/isoforms in Taiwanese women with breast cancer.

AIM: To quantify ER variants/isoforms for women with breast cancer in Taiwan, an area with remarkably low breast cancer rates, but with an early onset and poor prognosis. METHODS: Real-time PCR technology was exploited to quantify mRNAs of ERalpha, ERalphaE3Delta, ERalphaE5Delta, ERalphaE7Delta and ERbeta, in 49 breast cancer and paired adjacent normal tissues. Clinical parameters were assembled and tested for assocation with the ER expression. RESULTS: Comparison of cancer and matched normal samples showed significantly decreased ERbeta (p < 0.001) in cancer tissues, and constant amounts of ERalpha and their variants. The results revealed significantly lower ERalphaE7Delta/ERalpha (p = 0.030) and ERbeta/ERalpha (p = 0.035) ratios in patients with lymph node (LN) metastasis than in those without LN metastasis. CONCLUSION: Our data suggests that ERalphaE7Delta and ERbeta may regulate ERalpha in normal human breast tissue.

Toward developing a relative value scale for medical and surgical services.

A methodology has been developed to determine the relative values of surgical procedures and medical office visits on the basis of resource costs. The time taken to perform the service and the complexity of that service are the most critical variables. Inter-specialty differences in the opportunity costs of training and overhead expenses are also considered. Results indicate some important differences between the relative values based on resource costs and existing standards, prevailing Medicare charges, and California Relative Value Study values. Most dramatic are discrepancies between existing reimbursement levels and resource cost values for office visits compared to surgical procedures. These vary from procedure to procedure and specialty to specialty but indicate that, on the average, office visits are undervalued (or surgical procedures overvalued) four- to five-fold. After standardizing the variations in the complexity of different procedures, the hourly reimbursement rate in 1978 ranged from $40 for a general practitioner to $200 for surgical specialists.

The Chinese health care system: lessons for other nations.

This paper examines China's health care from a system perspective and draws some lessons for less developed nations. A decade ago, Chinese macro-health policy shifted its health care financing and delivery toward a free market system. It encouraged all levels of health facilities to rely on user fees to support their operations. However, China continued its administered prices and hospitals continued to be operated by the government. These financing, pricing and organizational policies were not coordinated. The author found these uncoordinated policies created serious dissonance in the system. Irrational prices distorted medical practices which resulted in overuse of drugs and high technology tests. Market-based financing created more unequal access to health care between the rich and poor. Public control of hospitals and poor management caused inefficiency, waste and poor quality of care. The disarray of the Chinese health system, however, had not caused a measurable decline in health status of the Chinese people. One explanation was that the government had maintained its level of funding (per capita) for public health and prevention. Another possible explanation was that rapid rising income in China had improved nutrition, clean water and education which offset any adverse impacts of poorer medical services to the low-income populations. Nonetheless, the Chinese experience showed that its increasing expenditure per person for health care through user fees and insurance had not produced commensurate improvement in health status. China'a experience holds several lessons for less developed nations. First, there is a close linkage between financing, price and organization of health care. Uncoordinated policies could exacerbate inequity and inefficiency in health care.(ABSTRACT TRUNCATED AT 250 WORDS)

The cost escalation of social health insurance plans in China: its implication for public policy.

China has been alarmed by its rapid rise in health care expenditures of social health insurance schemes. The health care expenditure per person for the 155 million people covered by the Chinese social insurance plans has been rising at an accelerative rate. We analyze why health care cost in China has risen, and show how other nations may benefit from this experience. The annual rate of increase in health expenditure per capita was only 3.1% during 1952 to 1978, the average rate rose to 8.2% during 1978 to 1985 and then 24.4% during 1985 to 1989. We found general inflation explained one-half of the high rates of increase between 1985-1989. Although China introduced patients co-payments in 1985, the residual expenditure per capita (after adjusting for general inflation and aging of the beneficiaries) increased at 7.4% per year due to the adoption of new technology, uses of more expensive drugs and increased quality of services. While we found the expenditure increases in China were largely caused by uncontrollable factors such as general inflation and aging of the population, we also found the change in Chinese hospital financing and payment policy caused rapid adoption of high-tech medicine and abusive usage of more expensive drugs which largely explained the annual increases in expenditures of 7.4% between 1985-1989. Chinese experience also shows that demand strategy (co-payment by patients) had very little effect to contain cost escalation.

Equity in health and health care: the Chinese experience.

This paper examines the changes in equality of health and health care in China during its transition from a command economy to market economy. Data from three national surveys in 1985, 1986, and 1993 are combined with complementary studies and analysis of major underlying economic and health care factors to compare changes in health status of urban and rural Chinese during the period of economic transition. Empirical evidence suggests a widening gap in health status between urban and rural residents in the transitional period, correlated with increasing gaps in income and health care utilization. These trends are associated with changes in health care financing and organization, including dramatic reduction of insurance cover for the rural population and relaxed public health. The Chinese experience demonstrates that health development does not automatically follow economic growth. China moves toward the 21st century with increasing inequality plaguing the health component of its social safety net system.

Transformation of China's rural health care financing.

In the late 1970s China launched its agricultural reforms which initiated a decade of continued economic growth and significant transformation of the Chinese society. The agricultural reforms altered the peasants' incentives, weakened community organization and lessened the central government's control over local communities. These changes largely caused the collapse of the widely acclaimed rural cooperative medical system in China. Consequently China experienced a decreased supply of rural health workers, increased burden of illnesses, disintegration of the three tier medical system, reduced primary health care, and an increased demand for hospital medical services. More than ten years have elapsed since China changed its agricultural economic system and China is still struggling to find an equitable, efficient and sustainable way of financing and organizing its rural health services. The Chinese experiences provided several important lessons for other nations: there is a need to understand the limits of the market forces and to redefine the role of the government in rural health care under a market economy; community participation in and control of local health financing schemes is essential in developing a sustainable rural health system; the rural health system needs to be dynamic, rather than static, to keep pace with changing demand and needs of the population.

Therapeutic lamellar keratectomy in the management of nontuberculous Mycobacterium keratitis refractory to medical treatments.

Nontuberculous Mycobacterium keratitis is characterized by its indolent course and poor response to antibiotic drugs. Between November 1989 and September 1993, 10 eyes diagnosed to have nontuberculous Mycobacterium keratitis underwent therapeutic lamellar keratectomy in conjunction with fortified topical medications. Nine operated eyes (90%) recovered with a shortened course and healed with an inactive scar. Six patients (60%) achieved a visual acuity of 20/40 or better postoperatively. For recalcitrant nontuberculous Mycobacterium keratitis, therapeutic lamellar keratectomy is highly recommendable for patients with intractable paracentral or peripheral ulcer, for uncompliant patients, for patients who cannot tolerate drug-induced ocular toxicity, or when penetrating keratoplasty is to be reserved for late rehabilitation of the eye.

Is community financing necessary and feasible for rural China?

The collapse of the Cooperative Medical System (CMS) in China after the agricultural reforms of the early 1980s caused serious concern and doubt about the viability of community financing of basic health care for the low-income population. This paper examines the rise and fall of China's community financing schemes and ascertains the need for and feasibility of community financing. Of the Chinese rural population, 90% now pay out-of-pocket for their health services. Both the problems with the fee-for-service system on the one hand and the observed advantages of the existing community financing schemes on the other indicate the necessity and desirability of revitalizing community financing as a major rural health care reform strategy. However, the feasibility of the community financing approach depends on adequate financial and social resources. Our study found that there are multiple potential funding sources for health care in rural areas, including households, village welfare funds, local enterprises, and the government. We designed several illustrative benefit packages and estimated their costs. It appears that a basic benefit package with high co-insurance would be affordable if funds could be mobilized from multiple sources. More importantly, community financing would require governmental promotion and support.

Benign retroperitoneal schwannoma mimicking a pancreatic cystic tumor: case report and literature review.

A rare case of benign retroperitoneal schwannoma mimicking a pancreatic cystic tumor is reported herein. The tumor mass, based on a computed tomography scan and an abdominal echo examination, was initially suspected to be a mucinous cystadenoma or cystadenocarcinoma of the pancreas. However, the surgical and pathohistological findings made a final diagnosis of benign pancreatic schwannoma. The patient is doing well at a 2-year follow-up. The tumor, 18x17x15 cm in size, represented the largest among reported pancreatic schwannomas. Furthermore, a comprehensive review of reported cases of pancreatic schwannoma was carried out to summarize corresponding findings, including benign or malignant forms, adherence to other tissues, cystic change of the tumor, as well as relation to von Recklinghausen's neurofibromatosis.

The impact of DRG payment on New Jersey hospitals.

Debate persists about the most effective way to pay hospitals to limit health care cost inflation. New Jersey, the first state to adopt the DRG payment system, has accumulated sufficient experience to allow a comparison of the relative efficacy of two reimbursement methods. Regression results, using a time trend specification, indicate that per case payment based on diagnosis related groups was no more successful in controlling hospital costs per capita than a previous per diem payment system. There were, however, significant changes in costs per case and length of stay. But the increase in admission rates neutralized the reduction in costs per case. There were no significant overall cost savings.

Economies of scope in physicians' work: the performance of multiple surgery.

While the fees for the large majority of physicians' services in the new Medicare Fee Schedule (MFS) are derived directly from studies of the resource costs involved, payments for one class of procedures, multiple surgery, are based instead on existing policies and conventions. Using surveys of physicians, we measured the work and time involved in performing 146 multiple surgeries. We found economies of scope exist in performing these services, particularly during the preoperative and postoperative periods. We also found some differences in economies across procedures. Based on our findings, we propose payment policies for multiple surgery.